title: Drug related genetic polymorphisms affecting adverse reactions to methotrexate, vinblastine, doxorubicin and cisplatin in patients with urothelial cancer.
abstract: OBJECTIVE
  There is considerable interindividual diversity in the development of adverse reactions during chemotherapy for cancers. This diversity is suggested to be attributable to differences in the disposition of chemotherapeutic agents, which is modified by genetic polymorphisms. In this study we evaluated the possible association of polymorphisms of genes involved in the metabolism, detoxification and transport of the agents with adverse reactions to methotrexate, vinblastine, doxorubicin and cisplatin therapy.
  
  
  METHODS
  A total of 40 patients with urothelial cancer who received methotrexate, vinblastine, doxorubicin and cisplatin or high dose methotrexate, vinblastine, doxorubicin and cisplatin chemotherapy between 1996 and 2005 at Akita University Medical Center were included in this study. Four genetic polymorphisms (ABCB1, GSTP1, CYP3A5 and MTHFR) and clinical parameters were included in the analysis to determine whether there was any association with the grade of adverse reactions at the first cycle and the worst grade of each adverse reaction throughout the chemotherapy period.
  
  
  RESULTS
  On multivariate analysis the CYP3A5 A6986G genotype *3/*3 (OR 8.205, 95% CI 1.616-41.667, p = 0.011) and smaller number of treatment cycles (OR 0.156, 95% CI 0.037-0.659, p = 0.011) were independent factors for leukocytopenia (grade 3 or greater) throughout the period of chemotherapy. The mean white blood cell count nadir in patients with genotype *3/*3 was significantly lower than that in those with the *1 allele (1,542 +/- 903 vs 2,431 +/- 973/mm(3), p = 0.009).
  
  
  CONCLUSIONS
  The A6986G polymorphism of CYP3A5, which is involved in the metabolism of vinblastine and doxorubicin, might be a genetic predictor of the severity of leukocytopenia induced by chemotherapy with methotrexate, vinblastine, doxorubicin and cisplatin.
authors.affiliation: Department of Urology, Akita University School of Medicine, Akita, Japan.
authors.forename: Norihiko
authors.initials: N
authors.lastname: Tsuchiya
authors.forename: Takamitsu
authors.initials: T
authors.lastname: Inoue
authors.forename: Shintaro
authors.initials: S
authors.lastname: Narita
authors.forename: Teruaki
authors.initials: T
authors.lastname: Kumazawa
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Saito
authors.forename: Takashi
authors.initials: T
authors.lastname: Obara
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Tsuruta
authors.forename: Yohei
authors.initials: Y
authors.lastname: Horikawa
authors.forename: Takeshi
authors.initials: T
authors.lastname: Yuasa
authors.forename: Shigeru
authors.initials: S
authors.lastname: Satoh
authors.forename: Tomonori
authors.initials: T
authors.lastname: Habuchi
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects* / Q000378:metabolism*; D002945:Cisplatin / Q000009:adverse effects / Q000378:metabolism; D004317:Doxorubicin / Q000009:adverse effects / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D008727:Methotrexate / Q000009:adverse effects / Q000378:metabolism; D008875:Middle Aged; D011110:Polymorphism, Genetic; D012189:Retrospective Studies; D014571:Urologic Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D014747:Vinblastine / Q000009:adverse effects / Q000378:metabolism
chemical_list: D014747:Vinblastine; D004317:Doxorubicin; D002945:Cisplatin; D008727:Methotrexate